This competing continuation application is divided into five projects and three cores. The program project has several major scientific aims. Since its inception, we have studied changes in central noradrenergic neurotransmission during aging. This includes studies of mechanisms at the molecular and cell biological levels, as well as studies of function in terms of effects on central neuronal physiology and correlation with motor learning. We propose to characterize changes in cholinergic neurotransmission in aging as well. This includes studies of the regulation of cholinergic neurons and their targets by trophic factors, as well as studies of the relationship between functional and cognitive alterations. We have proposed studies on long term potentiation, phosphorylation, and their regulation by excitatory and inhibitory amino acids in young and aged rats. We will also study the molecular biology of age-related receptor changes. A new focus of this grant is the study of calcium channel function and its relationship to neuronal degeneration. A second new focus involves study of free radical mechanisms in aged-related dysfunctions and their reversal by spin-trap compounds. Brain cell transplants will be utilized to differentiate between intrinsic and extrinsic determinants of age-related changes. Molecular biological and functional studies of trophic factors in the neurotrophin and TGF beta families are also proposed. The experiments in this program are multidisciplinary and interactive. Biochemical and electrophysiological measurements will be made in animal models. To the greatest extent possible, appropriate tissues from the same subjects studied physiologically will be examined biochemically.